Nodulosporic acid and related component nodulisporic acid A1 are antiparasitic agents and ectoparasiticidal agents isolated from the fermentation culture of Nodulisporiuim sp. MF-5954 (ATCC 74245). These three compounds have the following structures as disclosed in U.S. Pat. No. 5,399,582 and J. G. Ondeyka et al. J. Am. Chem. Soc. 1997, 119(38), 8809-8816. 
Derivatives of nodulisporic acid are disclosed in U.S. Pat. No. 5,962,499.
This invention relates to new acaricidal, antiparasitic, insecticidal and anthelmintic agents related to the nodulisporic acids, to processes for their preparation, compositions thereof, their use in the treatment of parasitic infections, including helminthiasis, in human and animals, and their use in the treatment of parasitic infections in plants or plant products.
The present invention provides compounds having the formula I: 
wherein  represents a single or a double bond;
X is (1) a bond, or
(2) C(Rx)(Ry);
Y is (1) a bond, or
(2) C(Rx)(Ry);
Z is (1) H,
(2) C(Rx)(Ry)(Rz),
(3) a group selected from Rz; or
Xxe2x80x94Y is (1) C(Rx)xe2x95x90C(Rx) or
(2) Cxe2x89xa1C, or
Yxe2x80x94Z is (1) C(Rx)xe2x95x90C(Rx)(Rz) or
(2) Cxe2x89xa1C(Rz);
R1 is (1) hydrogen,
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C2-C10 alkenyl,
(4) optionally substituted C2-C10 alkynyl,
(5) optionally substituted C3-C8 cycloalkyl,
(6) optionally substituted C5-C8 cycloalkenyl,
(7) optionally substituted aryl,
(8) optionally substituted 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NRc,
where the substitutents on the alkyl, alkenyl, alkynyl are 1 to 3 groups selected from Rxe2x80x2, the substituents on aryl is 1 to 3 groups selected from Rxe2x80x3, and the substituents on cycloalkyl and cycloalkenyl are 1 to 3 groups independently selected from Rxe2x80x3, oxo and thiono;
R2, R3, and R4 are independently ORa, OCO2Rb, OC(O)NRcRd; or
R1+R2 represent xe2x95x90O, xe2x95x90NORa, xe2x95x90Nxe2x80x94NRcRd, xe2x95x90CRaCO2Ra, xe2x95x90CRaC(O)NRcRd, xe2x95x90CRaCN, xe2x95x90CRaC(O)Ra, or xe2x95x90CRaRa;
R5 is (1) hydrogen,
(2) ORa or
R4+R5 represent xe2x95x90O, xe2x95x90NORa, xe2x95x90Nxe2x80x94NRcRd or xe2x95x90CRaRa;
Ra is (1) H,
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C3-C10 alkenyl,
(4) optionally substituted C3-C10 alkynyl,
(5) optionally substituted C3-C15 cycloalkyl,
(6) optionally substituted C5-C10 cycloalkenyl,
(7) optionally substituted aryl,
(8) optionally substituted heteroaryl,
(9) optionally substituted 3- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from O, S and NRg,
(10) a benzene ring fused to a 4- to 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and NRg,
(11) a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NRg fused to a 4- or 8-membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and NRg, and
where the substituents on the aryl, alkyl, alkenyl, alkynyl groups are 1 to 10 groups selected from Rxe2x80x2; the substituents on aryl, heteroaryl and benzene are 1 to 5 groups selected from Rxe2x80x3; and the substituents on cycloalkyl, cycloalkenyl and heterocycle are 1 to 10 groups selected from Rxe2x80x3, oxo and thiono;
Rb is (1) a group selected from Ra,
(2) optionally substituted C2-C6 alkanoyl,
Rc and Rd are independently selected from Rb, hydroxy, C1-C5alkoxy, C1-C5alkoxycarbonyl, aminocarbonyl, C1-C5alkylaminocarbonyl and C1-C5dialkylaminocarbonyl; or
Rc and Rd together with the N to which they are attached form a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, said ring is optionally substituted with 1 to 5 groups independently selected from Rxe2x80x3, thiono and oxo; said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from Re; said ring is further optionally spirofused to a C3-C7cycloalkyl ring:
Re is (1) halogen,
(2) C1-C7 alkyl,
(3) C1-C3 perfluoroalkyl,
(4) S(O)mRi,
(5) cyano,
(6) nitro,
(7) RiO(CH2)vxe2x80x94,
(8) RiCO2(CH2)vxe2x80x94,
(9) RiOCO(CH2)v,
(10) optionally substituted aryl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy,
(11) SO2NRiRi, or
(12) amino;
Rf is (1) H,
(2) C1-C5alkyl optionally substituted with 1 to 5 groups selected from halogen, cyano, hydroxy, C1-C3alkoxy, NRgRh, CO2Ri and CONRgRh,
(3) C2-6alkenyl,
(4) C2-6alkynyl,
(5) C3-C6cycloalkyl,
(6) aryl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy, or
(7) aryl-C1-C3alkyl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy, or
two Rf groups together with the nitrogen atom to which they are attached form a a 3-to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRg, said ring is optionally substituted with 1 to 5 groups independently selected from Rxe2x80x3, thiono and oxo; said ring is further optionally fused to a benzene ring optionally substituted with 1 to 3 groups selected from Re; said ring is further optionally spirofused to a C3-C7cycloalkyl ring;
Rg and Rhare independently
(1) hydrogen,
(2) C1-C10 alkyl optionally substituted with 1 to 10 groups selected from hydroxy, amino, C(O)Ri, and CO2Ri,
(3) aryl optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl and C1-C3 perfluoroalkyl,
(4) aryl C1-C6 alkyl, wherein the aryl is optionally substituted with 1 to 5 groups selected from halogen, amino, 1,2-methylenedioxy, C1-C7 alkoxy, C1-C7 alkyl and C1-C3 perfluoroalkyl,
(5) C3-C7cycloalkyl optionally substituted with phenyl,
(6) C1-C5 alkanoyl,
(7) C1-C5 alkoxycarbonyl,
(8) aryl C1-C5 alkoxycarbonyl,
(9) aminocarbonyl,
(10) C1-C5 monoalkylaminocarbonyl
(11) C1-C5 dialkylaminocarbonyl; or
Rg and Rh together with the N to which they are attached form a 3- to 7-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m, and NRi, optionally substituted with 1 to 3 groups independently selected from Re and oxo;
Ri is (1) hydrogen,
(2) C1-C3 perfluoroalkyl,
(3) C1-C6 alkyl,
(4) optionally substituted aryl C0-C6 alkyl, where the aryl substituents are from 1 to 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy;
Rx and Ry are independently selected from the group consisting of
(1) hydrogen
(2) optionally substituted C1-C10 alkyl,
(3) optionally substituted C2-C10 alkenyl,
(4) optionally substituted C2-C10 alkynyl, wherein the substituents on alkyl, alkenyl and alkynyl are 1 to 5 groups independently selected from Rxe2x80x2,
(5) a group selected from Rz, or
Rx+Ry is (1) xe2x95x90NORa,
(2) xe2x95x90NNRcRd,
(3) xe2x95x90NNRcSO2Ra,
(4) xe2x95x90CRaCO2Ra, or
(5) xe2x95x90O,
Rz is (1) optionally substituted aryl,
(2) optionally substituted heterocyclyl,
(3) optionally substituted C3-C8 cycloalkyl,
(4) optionally substituted C5-C8cycloalkenyl,
(5) (CHRa)nORa,
(6) (CHRa)nOC(O)Ra,
(7) (CHRa)nOC(O)ORb,
(8) (CHRa)nOC(O)NRcRd,
(9) (CHRa)nOSO2Ra,
(10) (CHRa)nS(O)mRa,
(11) (CHRa)nSC(O)Ra,
(12) (CHRa)nNRcRd,
(13) (CHRa)nNRcC(O)Ra,
(14) (CHRa)nNRcC(O)ORa,
(15) (CHRa)nNRcC(O)C(O)ORa,
(16) (CHRa)nNRcC(O)NRcRd,
(17) (CHRa)nNRcSO2Ra,
(18) (CHRa)nNRcC(O)P(O)Ra,
(19) (CHRa)nNRcC(O)SRa,
(20) C(O)Ra,
(21) C(O)ORb,
(22) C(O)NRcRd,
(23) C(O)N(ORa)Rc,
(24) C(O)NRcNRcRd,
(25) C(O)NRcSO2Ra,
(26) halogen,
(27) CN,
(28) N3, 
(29) perfluoroalkyl,
(30) Nxe2x95x90Cxe2x95x90O,
(31) P(O)(ORa)2,
wherein the substituents on alkyl, alkenyl and alkynyl are 1 to 5 groups independently selected from Rxe2x80x2; the substituents on aryl are 1 to 3 groups independently selected from Rxe2x80x3; and the substituents on cycloalkyl and heterocyclyl are 1 to 5 groups independently selected from Rxe2x80x3, oxo and thiono;
Rxe2x80x2 is (1) halogen,
(2) cyano,
(3) nitro,
(4) C(O)Rf,
(5) CO2Rf,
(6) C(O)NRgRh,
(7) ORf,
(8) OC(O)Rf,
(9) OC(O)NRgRh,
(10) OC(O)ORf,
(11) SRf,
(12) S(O)m Rf,
(13) SO2NRgRh,
(14) NRgRh,
(15) NRgC(O)Rf,
(16) NRgCO2Rf,
(17) NRgC(S)ORf,
(18) NRgC(O)NRgRh,
(19) C3-C7 cycloalkyl optionally substituted with 1 to 4 groups independently selected from Re,
(20) C5-C7 cycloalkenyl optionally substituted with 1 to 4 groups independently selected from Re,
(21) aryl optionally substituted with 1 to 4 groups independently selected from Re, or 2 adjacent substituents together form methylenedioxy,
(22) heteroaryl optionally substituted with 1 to 4 groups independently selected from Re,
(23) 5 to 9-membered heterocycle containing from 1 to 4 heteroatoms independently selected from O, S and NRg, and optionally substituted with 1 to 4 groups independently selected from Re,
Rxe2x80x3 is (1) a group selected from Rxe2x80x2,
(2) C1-C6 alkyl, optionally substituted with halogen, aryl, ORf and NRgRh,
(3) C2-6alkenyl,
(4) C2-6alkynyl;
m is 0 to 2;
n is 0or 1; and
v is 0 to 3; or
a pharmaceutically acceptable salt thereof; and with the proviso that when Xxe2x80x94Y is CHxe2x95x90CH or CH2xe2x80x94CH2, then Z is not C(O)H.
In one subset of the present invention are compounds of formula Ia: 
wherein Rx, Ry and Rz are as defined under formula I. In one embodiment, Rx is H, Ry is selected from H, CONRcRd, optionally subsituted aryl and optionally substituted C1-C6alkyl, and Rz is selected from the group consisting of (CHRa)nORa, (CHRa)nOC(O)Ra, (CHRa)nOC(O)ORb, (CHRa)nOC(O)NRcRd, (CHRa)nOSO2Ra, (CHRa)nS(O)mRa, (CHRa)nSC(O)Ra, (CHRa)nNRcRd, (CHRa)nNRcC(O)Ra, (CHRa)nNRcC(O)ORa, (CHRa)nNRcC(O)C(O)ORa, (CHRa)nNRcC(O)NRcRd, (CHRa)nNRcSO2Ra, (CHRa)nNRcC(O)P(O)Ra, (CHRa)nNRcC(O)SRa, C(O)Ra, C(O)ORb, C(O)NRcRd, C(O)N(ORa)Rc, C(O)NRcNRcRd, C(O)NRcSO2Ra wherein Ra, Rb, Rc, Rd and n are as defined under formula I. In another embodiment, Rx+Ry is oxo, and Rz is selected from C(O)Ra, C(O)ORb, C(O)NRcRd, C(O)N(ORa)Rc, C(O)NRcNRcRd, C(O)NRcSO2Ra wherein Ra, Rb, Rc and Rd are as defined under formula I.
Within formula Ia, there is a subset of compounds having the formula Ia(1): 
wherein Rc and Rd are as defined under formula I. In one embodiment Rc and Rd are independently H, C1-C6 alkyl or C3-C6alkenyl. In another embodiment Rc and Rd together complete a 5- or 6-membered ring containing one other heteroatom selected from O, S and NRg, and substituted by one or two oxo or thioxo groups, wherein said ring is optionally substituted by 1 to 3 groups selected from aryl and C1-C6alkyl, and is optionally benzofused or spirofused to a C3-C7cycloalkane, wherein said benzo and cycloalkane are optionally substituted with C1-C3alkylalkyl or aryl. More preferably the ring is represented as follows: 
wherein X is O or S, Y is O, S or NRg, Rg is as defined under formula I, and the two R groups are independently H or C1-C5alkyl, or together complete a C3-C6 ring.
Anothere subset within formula Ia are compounds having the formula Ia(2): 
wherein Rz is ORa, OC(O)Ra, OC(O)ORb, OC(O)NRcRd, NRcC(O)Ra, NRcC(O)ORa, NRcC(O)NRcRd, NRcSO2Ra.
In another subset of formula I are compounds of formula Ib: 
wherein Rz is as defined under formula I. In one embodiment Rz is selected from optionally substituted heterocycle, optionally substituted aryl, CO2Rb, CONRcRd, NRcC(O)Ra, NRcC(O)ORa, NRcC(O)NRcRd. In another embodiment Rz is selected from optionally substituted oxazolinyl, thiazolinyl, thiazoly and oxazolyl.
One subset of formula Ib are compounds of formula Ib(1) 
wherein Rxe2x80x3(a) is selected from H, C1-C6alkyl optionally substituted with halogen, aryl, ORf, or NRgRh, C3-C7cycloalkyl optionally substituted with 1 or 2 groups independently selected from Re, and aryl optionally substituted with 1 or 2 groups independently selected from Re.
Another subset of formula Ib are compounds of formula Ib(2) 
wherein Rg is as defined under formula I, and the two Rxe2x80x3(b) groups are independently H or Rxe2x80x3 as defined under formula I.
In a preferred embodiment compounds of formula I have the following stereoconfiguration and substituent: 
wherein X, Y and Z are as defined under formula I.
The present invention provides in another aspect pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. Such compositions may further comprise one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.
The present invention provides in another aspect a method for treating parasitic diseases in a mammal which comprises administering an antiparasitic amount of a compound of Formula I. The treatment may further comprise co-administering one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.
xe2x80x9cAlkylxe2x80x9d as well as other groups having the prefix xe2x80x9calkxe2x80x9d, such as alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. xe2x80x9cAlkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and other like terms include carbon chains containing at least one unsaturated Cxe2x80x94C bond.
The term xe2x80x9ccycloalkylxe2x80x9d means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as benzofused carbocycles. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, xe2x80x9ccycloalkenylxe2x80x9d means carbocycles containing no heteroatoms and at least one non-aromatic Cxe2x80x94C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
The term xe2x80x9chalogenxe2x80x9d is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
The term xe2x80x9cheterocyclexe2x80x9d, unless otherwise specfied, means mono- or bicyclic compounds that are saturated or partly unsaturated, as well as benzo- or heteroaromatic ring fused saturated heterocycles or partly unsaturated heterocycles, and containing from 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen. Examples of saturated heterocycles include morpholine, thiomorpholine, piperidine, piperazine, tetrahydropyran, tetrahydrofuran, dioxane, tetrahydrothiophene, oxazolidine, pyrrolidine; examples of partly unsaturated heterocycles include dihydropyran, dihydropyridazine, dihydrofuran, dihydrooxazole, dihydropyrazole, dihydropyridine, dihydropyridazine and the like. Examples of benzo- or heteroaromatic ring fused heterocycle include 2,3-dihydrobenzofuranyl, benzopyranyl, tetrahydroquinoline, tetrahydroisoquinoline, benzomorpholinyl, 1,4-benzodioxanyl, 2,3-dihydrofuro(2,3-b)pyridyl and the like.
The term xe2x80x9carylxe2x80x9d is intended to include mono-, bi- and tricyclic aromatic and heteroaromatic rings containing from 0 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term xe2x80x9carylxe2x80x9d is also meant to include benzofused cycloalkyl, benzofused cycloalkenyl, and benzofused heterocyclic groups. Examples of xe2x80x9carylxe2x80x9d groups include phenyl, pyrrolyl, isoxazolyl, pyrazinyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furo(2,3-B)pyridyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzothiophenyl, quinolinyl, indolyl, 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like.
Examples of NRcRd or NRgRh forming a 3- to 10-membered ring containing 0 to 2 additional heteroatoms selected from O, S(O)m and N are aziridine, azetidine, pyrrolidine, piperidine, thiomorpholine, morpholine, piperazine, octahydroindole, tetrahydroisoquinoline and the like.
The term xe2x80x9coptionally substitutedxe2x80x9d is intended to include both substituted and unsubstituted; thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
The term xe2x80x9ccompositionxe2x80x9d, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other, thus, for example, ORa at C7 may represent OH and at C24 represent O-acyl.
Compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is intended to include all possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and all possible geometric isomers. In addition, the present invention includes all pharmaceutically acceptable salts thereof. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
Compounds of the present invention are named based on the trivial name of the parent compound, nodulisporic acid (compound A), and their position numbers are those as indicated for nodulisporic acid A.
Compounds of the present invention are prepared from nodulisporic acids A and A1 (Compounds A and B), which in turn are obtained from the fermentation culture of Nodulisporium sp. MF-5954 (ATCC 74245). The description of the producing microorganism, the fermentation process, and the isolation and purification of the three nodulisporic acids are disclosed in U.S. Pat. 5,399,582, issued Mar. 21, 1995, which is hereby incorporated by reference in its entirety.
The above structural formula is shown without a definitive stereochemistry at certain positions. However, during the course of the synthetic procedures used to prepare such compounds, or using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereolsomers. In particular, the stereoisomers at C7, C24, C1xe2x80x2, C2xe2x80x2, C1xe2x80x3, C2xe2x80x3, C3xe2x80x3, C4xe2x80x3 and C5xe2x80x3 may be oriented in either the alpha- or beta-position, representing such groups oriented below or above the plane of the molecule, respectively. In each such case, and at other positions in the molecule, both the alpha- and beta-configurations are intended to be included within the ambit of this invention.
Compounds of formula I wherein the allyl group at position 2xe2x80x2 is in the epi configuration may be obtained by treatment of the appropriate precursor with a bases such as hydroxide, methoxide, imidazole, triethylamine, potassium hydride, lithium diisopropylamide and the like in protic or aprotic solvents (as appropriate) such as water, methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide and the like. The reaction is complete at temperatures from xe2x88x9278xc2x0 C. to the reflux temperature of the solution in from 15 minutes to 12 hours.
During certain reactions described below, it may be necessary to protect the groups at C24 and C7. With these positions protected, the reactions may be carried out at other positions without affecting the remainder of the molecule. Subsequent to any of the described reactions (vida infra), the protecting group(s) may be removed and the unprotected product isolated. The protecting groups employed at C24 and C7 are those which may be readily synthesized, not significantly affected by the reactions at the other positions, and may be removed without significantly affecting any other functionality of the molecule. One preferred type of protecting group is the tri-substituted silyl group, preferably the tri-loweralkyl silyl group or di-loweralkyl-aryl silyl group. Especially preferred examples are the trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and dimethylphenylsilyl groups.
The protected compound may be prepared with the appropriately substituted silyl trifluoromethanesulfonate, BSTFA, hexamethyldisilazane or silyl halide, preferably the silyl chloride. The reaction is carried out in an aprotic solvent such as methylene chloride, benzene, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, dimethylformamide and the like. In order to minimize side reactions, there is included in the reaction mixture a base to react with the acid released during the course of the reaction. Preferred bases are amines such as imidazole, pyridine, triethylamine or dilsopropylethylamine and the like. The base is required in amounts equimolar to the amount of hydrogen halide liberated, however, generally several equivalents of the amine are employed. The reaction is stirred at from 0xc2x0 C. to the reflux temperature of the reaction mixture and is complete from 1 to 24 hours.
The silyl group is removed by treatment of the silyl compound with anhydrous pyridine-hydrogen fluoride in tetrahydrofuran or dimethylsulfoxide or with tetraalkylammonium fluoride in tetrahydrofuran. The reaction is complete in from 1 to 24 hours at from 0xc2x0 C. to 50xc2x0 C. Alternatively, the silyl group may be removed by stirring the silylated compound in lower protic solvents such as methanol, ethanol, isopropanol and the like catalyzed by an acid, preferably a sulfonic acid monohydrate such as para-toluenesulfonic acid, benzenesulfonic acid, pyridinium para-toluenesulfonate or carboxylic acids such as acetic acid, propionic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid and the like. The reaction is complete in 1 to 24 hours at from 0xc2x0 C. to 50xc2x0 C.
Protecting groups that may also be suitably used in the preparation of compounds of the present invention may be found in standard textbooks such as Greene and Wutz, Protective Groups in Organic Synthesis, 1991, John Wiley and Sons, Inc.
Compounds of formula I where R1 and R2 together represent an oxime, xe2x95x90NORa, may be prepared by treating the appropriate oxo analog with H2NORa to produce the corresponding oxime. Oxime formation may be accomplished using techniques known to those skilled in the art, including, but not restricted to, the use of H2NORa either as the free base or as an acid addition salt such as the HCl salt, or an O-protected hydroxylamine such as O-trialkylsilylhydroxylamine, in a protic solvent such as methanol, ethanol, isopropanol and the like or aprotic solvents such as methylene chloride, chloroform, ethyl acetate, isopropyl acetate, tetrahydrofuran, dimethylformamide, benzene, toluene and the like, as appropriate. The reactions may by catalyzed by the addition of sulfonic acids, carboxylic acids or Lewis acids, including, but not limited to, benzenesulfonic acid monhydrate, para-toluenesulfonic acid monohydrate, acetic acid, zinc chloride and the like.
Similarly, compounds of formula I wherein R1 and R2 together represent xe2x95x90NNRcRd may be prepared by treating the appropriate oxo analog with H2NNRcRd to give the corresponding hydrazones using conditions directly analogous to those described for oxime formation.
Compounds of formula I wherein one or both of the  bonds represent a single bond may be prepared from the corresponding compound wherein  is a double bond by conventional hydrogenation procedures. The double bonds may be hydrogenated with any of a variety of standard precious metal hydrogenation catalysts such as Wilkinson""s catalyst, Pearlman""s catalyst, 1-25% palladium on carbon, 1-25% platinum on carbon and the like. The reaction is generally carried out in a non-reducible solvents (either protic or aprotic) such as methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, benzene, toluene, dimethylformamide and the like. The hydrogen source may be hydrogen gas from 1 to 50 atmospheres of pressure or other hydrogen sources such as ammonium formate, cyclohexene, cyclohexadiene and the like. The reduction also may be carried out using sodium dithionite and sodium bicarbonate in the presence of a phase transfer catalyst, in particular a tetraalkylammonium phase transfer catalyst, and the like. The reactions may be run from 0xc2x0 C. to 100xc2x0 C. and are complete in from 5 min to 24 hours.
Compounds of formula I wherein R2 is OH and R1 is H may be prepared from the corresponding ketone by treating the appropriate oxo analog with standard reducing agents including, but not restricted to, sodium borohydride, lithium borohydride, lithium aluminum hydride, potassium tri-sec-butyl borohydride, diisobutylaluminum hydride, diborane oxazaborolidines and alkylboranes (both achiral and chiral). These reactions are performed in a manner known to those skilled in the art and are carried out in non-reducible solvents such as methanol, ethanol, diethyl ether, tetrahydrofuran, hexanes, pentane, methylene chloride and the like. The reactions are complete in from 5 minutes to 24 hours at temperatures ranging from xe2x88x9278xc2x0 C. to 60xc2x0 C. Compounds of formula I wherein R2 is OH, R1 is H and Rz contains CH2OH may be obtained by reacting the appropriate carboxylic acid or ester analog (e.g., where Rz contains CO2H or CO2Rb) with the more reactive reducing agents as described above, including lithium aluminum hydride, lithium borohydride and the like. Compounds of formula I wherein R2 and R1 together are oxo and Rz contains CH2OH may be obtained by reacting the appropriate carboxylic acid (e.g., where Rz contains CO2H) with less reactive reducing agents such as diborane and the like.
Compounds of formula I wherein R2 is OH and R1 is other than H, may be prepared from the corresponding ketone by treating the appropriate oxo analog with a Grignard reagent R1MgBr, or with a lithium reagent R1Li. These reactions are performed in a manner known to those skilled in the art and preferably are performed in aprotic solvents such as diethyl ether, tetrahydrofuran, hexanes or pentanes. The reactions are complete in from 5 minutes to 24 hours at temperatures ranging from xe2x88x9278xc2x0 C. to 60xc2x0 C.
The 3xe2x80x3- and/or 1xe2x80x3-aldehydes (compounds 1 and 2, respectively) may be prepared as described in Scheme I. Thus, compound A may be treated with potassium permanganate under conditions known to those skilled in the art to yield the desired 3xe2x80x3- and 1xe2x80x3-aldehyde products. The potassium permanganate may be used stoichiometrically or in excess and in the presence of a solid support including but not restricted to, Celite, basic alumina, neutral alumina, acidic alumina, silica gel, clays and the like. Sodium permanganate or tetraalkylammonium permanganate (either preformed or generated in situ from a tetraalkylamonium salt and potassium permanganate) may be substituted for potassium permanganate. Suitable tetraalkylammonium salts include, but are not restricted to (n-Bu)4NX, (PhCH2)3NMeX, (n-heptyl)4NX, (PhCH2)N(n-Bu)3X, (n-dodecyl)3NMeX, Adogen 464 and the like and where X=HO, SO4, PF6 and the like. The reaction to form aldehydes 1 and 2 may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methylene chloride, chloroform, dichloroethane, +methanol, ethanol, tert-butanol, ether, tetrahydrofuran, benzene, pyridine, acetone and the like. The reactions may be performed at from xe2x88x9278xc2x0 C. to 80xc2x0 C. and are complete in from 5 minutes to 24 hours. 
Aldehydes 1 and 2 may also be produced by treating compound 3 with osmium tetroxide under conditions known to those skilled in the art as shown in Scheme II below. Also produced during this reaction is the diol product 4. Mono- and di-substituted amides of compound 3 may be used in this reaction. These include, but are not restricted to, monosubstituted amides such as N-methyl, N-ethyl, N-propyl, N-butyl, tert-butyl, N-phenyl and the like or disubstituted amides such as N,N-dimethyl, N,N-diethyl, N-methyl-N-ethyl, N-methyl-N-phenyl and the like. Osmium tetroxide may be used either stoichiometrically or catalytically in the presence of an oxidant, including, but not restricted to, morpholine N-oxide, trimethylamine N-oxide, hydrogen peroxide, tert-butyl hydroperoxide and the like. The dihydroxylation reactions may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methanol, ethanol, tert-butanol, ether, tetrahydrofuran, benzene, pyridine, acetone and the like. The reactions may be performed at from xe2x88x9278xc2x0 C. to 80xc2x0 C. and are complete in from 5 minutes to 24 hours. Diol product 4 may be converted into aldehydes 1 and 2 by treatment with an oxidizing agent, including, but restricted to, NaIO4, HIO4, MnO2, Amberlite 904-NaIO4 and the like, or preferably Pb(OAc)4. These oxidative cleavage reactions may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methanol, ethanol, tert-butanol, ether, tetrahydrofuran, benzene, pyridine, acetone and the like. The reactions may be performed at from xe2x88x9278xc2x0 C. to 80xc2x0 C. and are complete in from 5 minutes to 24 hours. 
Compounds of formula I where Rz is CO2H are prepared from the 3xe2x80x2-aldehdye of compound 1. The 3xe2x80x3-aldehyde of compound 1 may be oxidized to generate the corresponding 3xe2x80x3-carboxylic acid (compound 5) using standard oxidizing conditions known to those skilled in the art. The reaction is carried out using at least one equivalent of an oxidant in protic or aprotic solvents. Oxidizing agents include, but are not restricted to, AgO/NaCN, NBS/H2O, NaClO2/isoprene, MnO2, MnO2/NaCN, NaClO2/(K)NaH2PO4/isoprene, and the like. These oxidation reactions may be performed in solvents or mixtures of solvents including but not restricted to, chloroform, carbon tetrachloride, water, tetrahydrofuran, benzene, ethyl acetate, isopropyl acetate and the like, or most preferably methylene chloride and the reaction proceeds from temperatures of 0xc2x0 C. to 75xc2x0 C. 
Compounds of formula I where Rz contains C(O)N(ORb)Rc or C(O)NRcRd (such as compound 6) are prepared from the corresponding carboxylic acid (such as compound 5) using standard amide-forming reagents known to those skilled in the art. The reaction is carried out using at least one equivalent of an amine nucleophile, HN(ORb)Rc or HNRcRd, although preferably ten to one hundred equivalents of amine nucleophiles are employed. Amide-forming reagents include, but are not restricted to, dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorphosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), chloro-tris-pyrrolidino-phosphonium hexafluorophosphate (PyCloP), bromo-tris-pyrrolidino-phosphonium hexafluoro-phosphate (PyBroP), diphenylphosphoryl azide (DPPA), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-bis(pentamethylene)uronium hexafluorophosphate and 2-chloro-1-methyl-pyridinium iodide. The amide-forming reactions may be facilitated by the optional addition of N-hydroxybenzotriazole or N-hydroxy-7-aza-benzotriazole. The amidation reaction is generally performed using at least one equivalent (although several equivalents may be employed) of amine bases such as triethylamine, diisopropyl-ethylamine, pyridine, N,N-dimethylaminopyridine and the like. The carboxyl group may be activated for amide bond formation via its corresponding acid chloride or mixed anhydride, using conditions known to those skilled in the art. These amide-forming reactions are carried out in aprotic solvents such as methylene chloride, tetrahydrofuran, diethyl ether, dimethylformamide, N-methylpyrrolidine and the like at xe2x88x9220xc2x0 C. to 60xc2x0 C. and are complete in 15 minutes to 24 hours.
Compounds of formula I where Rz contains CO2Rb (such as compound 7) are prepared from the corresponding carboxylic acid (such as compound 5) using standard ester-forming reagents known to those skilled in the art. The esterification reaction is carried out using at least one equivalent of an alcohol, HORb, although preferably ten to one hundred equivalents of alcohol are used; the esterification also may be carried out using the alcohol as solvent. Esterification reagents include, but are not restricted to, dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), diisopropylcarbodiimide, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorphosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), chloro-tris-pyrrolidinophosphonium hexafluorophosphate (PyCloP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), diphenylphosphoryl azide (DPPA), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-bis(pentamethylene)uronium hexafluorophosphate and 2-chloro-1-methylpyridinium iodide. The ester-forming reactions may be facilitated by the optional addition of N-hydroxybenzotriazole, N-hydroxy-7-aza-benzotriazole, 4-(N,N-dimethylamino)pyridine or 4-pyrrolidinopyridine. The reaction is generally performed using at least one equivalent (although several equivalents may be employed) of amine bases such as triethylamine, dilsopropylethylamine, pyridine and the like. The carboxyl group may be activated for ester bond formation via its corresponding acid chloride or mixed anhydride, using conditions known to those skilled in the art. These ester-forming reactions are carried out in aprotic solvents such as methylene chloride, tetrahydrofuran, diethyl ether, dimethylformamide, N-methylpyrrolidine and the like at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. and are complete in 15 minutes to 24 hours.
Compounds of formula I wherein one or more of R2, R3, and R4 is ORa, OCO2Rb or OC(O)NRcRd, and/or where Z is CH2ORa, CH2OCO2Rb or CH2OC(O)NRcRd may be prepared using known methods for acylation, sulfonylation and alkylation of alcohols. Thus, acylation may be accomplished using reagents such as acid anhydrides, acid chlorides, chloroformates, carbamoyl chlorides, isocyanates and amine bases according to general procedures known to those skilled in the art. Sulfonylations may be carried out using sulfonyl chlorides or sulfonic anhydrides. The acylation and sulfonylation reactions may be carried out in aprotic solvents such as methylene chloride, chloroform, pyridine, benzene, toluene and the like. The acylation and sulfonylation reactions are complete in from 15 minutes to 24 hours at temperatures ranging from xe2x88x9220xc2x0 C. to 80xc2x0 C. The degree of acylation, sulfonylation and alkylation will depend on the amount of the reagents used. Thus, for example, using one equivalent of an acylating reagent and one equivalent of nodulisporic acid results in a product mixture containg 4- and 20-acylated nodulisporic acid; such a mixture may be separated by conventional techniques such as chromatography.
Compounds of formula I wherein one or more of R2, R3, R4 is ORa and/or where Rx contains CH2ORa, may be prepared using methods known to those skilled in the art for the alkylation of alcohols. Thus, alkylation may be accomplished using reagents including, but not restricted to, halides IRa, BrRa, ClRa, diazo reagents N2Ra, trichloroacetimidates RaOC(NH)CCl3, sulfates RaOSO2Me, RaOSO2CF3, and the like. The alkylation reactions may be facilitated by the addition of acid, base or Lewis acids, as appropriate. The reactions are performed in aprotic solvents such as methylene chloride, chloroform, tetrahydrofuran, benzene, toluene, dimethylformamide, N-methyl-pyrrolidine, dimethyl sulfoxide, hexamethylphosphoramide and are complete at from 0xc2x0 C. to the reflux temperature of the solution from 15 minutes to 48 hours.
Compounds of formula I may be prepared where Z is CH2OH (e.g. compound 8) may be prepared by treatment of compound 1 with appropriate reducing agents (Scheme IV). Suitable hydride sources include, but are not limited to NaBH4, NaCNBH3, LiBH4, LiAlH4, NaBH(OAc)3, DIBAL-H, nBu3SnH, Et3SiH, diborane, Alpine borane, BH3.Me2S, L-Selectride, alkyl borane reagents, or most preferably, 9-BBN. The reduction reaction may be performed in protic or aprotic solvents, or mixtures of solvents, and include, but are not limited to, methanol, ethanol, methylene chloride, toluene, diethyl ether, dioxane and the like, or most preferable, THF and the reactions are conducted from xe2x88x9278xc2x0 C. to 100xc2x0 C. and are complete in from 2 minutes to 24 hours. Starting compound 1 may have its C7- and C24-hydroxyl groups protected with silyl protecting groups. The newly formed 3xe2x80x3-hydroxyl of compounds of formula 8 may be acylated with suitable acylating agents including, but not restricted to, acid chlorides, carbamoyl chlorides, isocyanates, chloroformates, carboxylic acids, sulfonyl chlorides and the like as described previously. 
Compound 1 may be converted to compound 9 using appropriate olefin-forming reaction conditions known to those skilled in the art as shown in Scheme V. Reagents for these reactions include, but are not restricted to, the use of stabilized and unstabilized Wittig reagents, Horner-Emmons reagents, Tebbe reagent, Petassis reagent, aldol reactions, Knoevenagel reactions, Peterson olefinations and the like. Starting compound 1 may have its C7- and C24-hydroxyl groups protected with silyl protecting groups. The compounds of formula 9 shown below may be acyclic or cyclic, depending on the chain-extending reagents utilized. Alternatively, compounds of formula 9 may be acyclic but further modified to yield cyclic products. Wittig reagents may be readily prepared by reacting Ph3P with an appropriate halide under conditions known to those skilled in the art, such as those described by Ikuta, H. et al. (J. Med. Chem. 1987, 30, 1995-1998) or Larock, R. C. (Comprehensive Organic Transformations, VCH Publishers, Inc.: New York, N.Y., 1989, Chapter 4). Alternatively, stabilized Wittig reagents may be prepared as described by Bestmann, H. J. and Schulz, H. (Chem. Ber. 1964, 97, 11) wherein an appropriate unstabilized Wittig reagent Ph3Pxe2x95x90C(Ra)2 is reacted with a suitable chloroformate to yield Ph3Pxe2x95x90C(Ra)2CO2Rb or as described by the conjugate addition of Ph3P to Nxe2x80x94Rc substituted maleimides. The olefination reactions may be performed in a variety of solvents or mixtures of solvents. These include both protic and aprotic solvents such as water, methanol, ethanol, tert-butanol, ether, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, pyridine, acetone and the like. Suitable bases include, but are not limited to, NaOH, KOH, NaOEt, KOtBu, LDA, LHMDS, NaHMDS, KHMDS, pyridine, piperidine, morpholine, lutidine, DMAP, DBU and the like. The reactions may be performed at from xe2x88x9278xc2x0 C. to 120xc2x0 C. and are complete in from 5 minutes to 24 hours. The compounds of formula 9 may be further elaborated by Stille, Heck and Suzuki couplings where R6 contains OTf, B(OH)2, Sn(n-Bu)3, SnMe3, OP(O)(OPh)2, I, Br, or Cl. 
Compounds of formula 9 are useful as intermediates in the preparation of corresponding amides. The esters of compound 9 (where Rbxe2x89xa0H) may be hydrolyzed by treatment with hydroxide or ammonium hydroxide in a protic solvent such as methanol, ethanol, water, tetrahydrofuran/water or dimethylformamide/water and the like at from 0xc2x0 C. to the reflux temperature of the solution. Alternatively, the resultant esters may be transesterified by treatment with a Lewis acid, including, but not restricted to, magnesium chloride, magnesium bromide, aluminum chloride, zinc chloride, Otera""s catalyst, and the like, or preferably titanium tetra-isopropoxide in a protic solvent such as methanol, ethanol, isopropanol, 2-trimethylsilylethyl alcohol and the like, or preferably allyl alcohol. The transesterification reactions are complete in from 1 to 24 hours at 0xc2x0 C. to the reflux temperature of the solution, preferably 110xc2x0 C. The allyl ester (e.g. Rb=xe2x80x94CH2CHxe2x95x90CH2) may be removed by treatment with Pdxc2x0 using conditions known to those skilled in the are to generate the free carboxylic acid (e.g. Rb=H). Pdxc2x0 reagents include, but are not restricted to, PdCl2(PPh3)2, Pd(OAc)2(PPh3)2, PdCl2(PhCN)2, Pd(OAc)2, PdCl2(P(o-tolyl)3)2, PdCl2(DDPF), Pd2(dba)3, and the like, or preferably Pd(PPh3)4. The carboxylic acid of compound 9 may be converted into corresponding amides using conventional amide formation procedures as described (vida supra).
In Scheme VI, compound 9 (in which Rb is H) is treated with diphenylphosphoryl azide to provide an intermediate acyl azide (compound 10). Heating of compound 10 in an aprotic solvent such as benzene, toluene, dimethylformamide and the like results in a rearrangement yielding an isocyanate, compound 11. The isocyanate-forming reactions may be performed from 0xc2x0 C. to 120xc2x0 C., preferably at 80xc2x0 C., and are complete in 15 min to 24 hours. Compounds of formula 12 may be prepared when compounds of formula 11 are reacted with an appropriate amine HNRcRd in an aprotic solvent such as methylene chloride, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, benzene, toluene and the like. The urea-forming reactions may be performed from 0xc2x0 C. to 100xc2x0 C. and are complete in 15 minutes to 24 hours. Compounds of formula 11 may be reacted in an aprotic solvent such as benzene, toluene, methylene chloride, 1,2-dichloroethylene, dimethylformamide and the like, with an alcohol RbOH, such as methanol, ethanol, benzyl alcohol, 2-trimethylsilylethanol, 2,2,2-trichloroethanol, methyl glycolate, phenol and the like to yield carbamates of formula 13. Similarly, compounds of formula 14 may be prepared by substituting HSRb for HORb in the reaction. The addition of one or more equivalents of an amine base such as triethylamine, diisopropylethylamine, pyridine and the like may be employed to accelerate carbamate formation. The carbamate-forming reactions may be performed from 0xc2x0 C. to 100xc2x0 C. and are complete in 15 minutes to 24 hours. Compounds of formula 15 may be prepared by treatment of compounds of formula 11b with RaMgI, RaMgCl, RaLi, (Ra)2CuLi or preferably RaMgBr, as illustrated below. Compounds of formula 11 may be reacted in an aprotic solvent, or mixture of solvents, such as including, but not restricted to, dioxane, pentane, hexane, DMSO, HMPA, or NMP, and the like, or preferably tetrahydrofuran. The reactions may be performed from xe2x88x9278xc2x0 C. to 100xc2x0 C. and is complete in from 5 minutes to 12 hours. 
Compounds of formula 16 containing a ketone at C4xe2x80x3 may be prepared as illustrated in Scheme VI by acid-catalyzed hydrolysis of compounds of formula 11, 12, 13 or 14. Suitable acids for the hydrolysis include, but are not restricted to, p-toluenesulfonic acid, benzene sulfonic acid, acetic acid, proprionic acid, citric acid, camphor sulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or preferably, pyridium.p-toluenesulfonate. Suitable solvents for this hydrolsis include solvents, or mixtures of solvents, such as water, ethanol, n-propanol, iso-propanol, acetone, methylethyl ketone, methylene chloride, chloroform, toluene, tetrahydrofuran or dioxane and the like, or preferably methanol. The reactions may be performed from xe2x88x9220xc2x0 C. to 100xc2x0 C. or preferably at room temperature and are complete in from 5 min to 24 hours.
As illustrated in Scheme VII the procedure described in Scheme VI may be used to prepare compound 18 from compound 5a 
As shown in Scheme VIII, compounds may be prepared containing CO2Rb (compound 21a) or C(O)NRcRd (compound 21b) at C4xe2x80x3. Treatment of compound 1 with NCCH2Nxe2x95x90CPh2 and a base leads to the formation of compounds of formula 19. The reaction may be performed in solvents or mixtures of solvents including, but not limited to, diethyl ether, dioxane, dimethyl ether, NMP, DMSO, HMPA, methanol, ethanol, tert-butanol, water, benzene, toluene and the like, or most preferably tetrahydrofuran. Appropriate bases, or mixtures of bases, for performing the reaction include pyridine, piperidine, morpholine, Et3N, Et2NiPr, DBU, LDA, NaHMDS, KHMDS, NaOH, NaOEt, NaOtBu, KOtBu or most preferably LHMDS. The reaction may be performed at from xe2x88x9278xc2x0 C. to 50xc2x0 C., or most preferably xe2x88x9278xc2x0 C. The hydroxyl at C3xe2x80x3 of compounds of formula 19 may be sulfonylated directly or following isolation and/or purification using aryl- or alkylsulfonyl chlorides, aryl or alkylsulfonic anhydrides, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, or most preferably methanesulfonyl chloride in the presence of bases such as, but not limited to, pyridine, lutidine, DMAP, DIEA, DBU and the like, or most preferably Et3N. The reaction may be performed at from xe2x88x9278xc2x0 C. to 50xc2x0 C., or most preferably 0xc2x0 C. Formation of unsaturated compounds of formula 20 may be performed using by stirring compounds of formula 19 in lower protic solvents such as water, ethanol, isopropanol, propanol, allyl alcohol and the like or most preferably methanol, catalyzed by an acid, preferably a sulfonic acid monohydrate such as para-toluenesulfonic acid, benzenesulfonic acid, pyridinium para-toluenesulfonate or carboxylic acids such as acetic acid, propionic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, or inorganic acids such as HBF4, H2SO4 and the like or most preferably HCl. The reaction is complete in 1 to 24 hours at from 0xc2x0 C. to 50xc2x0 C. Compounds of formula 21a may be transesterification by heating 21a in an alcoholic solvent with a Lewis acid catalyst from 50xc2x0 C. to 200xc2x0 C., or most preferably 120xc2x0 C. Suitable alcohols include methanol, ethanol, allyl alcohol, propanol, benzyl alcohol, 2-trimethylsilylethylalcohol and the like. These reactions may also be performed using a co-solvent such as benzene or toluene. Suitable Lewis acids include MgCl2, MgBr2, AlCl3, ZnI2 and the like, or most preferably, Ti(OiPr)4. Standard conditions for these reactions are described in Seebach, D. et al., Synthesis (1982), 138-141. Deprotection of compounds of formula 21a where Rb is xe2x80x94CH2CHxe2x95x90CH2 will generate the corresponding carboxylic acid (e.g. compounds of formula 21a where Rb is a hydrogen) proceeds as described previously. The resultant carboxylic acid may be converted into the corresponding amides (compound 21b) using conditions previously described. 
Scheme IX illustrates an alternative method for the preparation of compounds of formula 21a. Acylation of compounds of formula 8 containing unsaturation at C1xe2x80x3-2xe2x80x3 leads to the formation of compounds of formula 22a and 22b. Suitable acylating agents include, but are not limited to, ethyl chloroformate, propylchloroformate, phenylch loroformate, para-nitrophenylchloroformate, dimethyl pyrocarbonate, diethyl pyrocarbonate, proprionyl chloride, acetic anhydride, proprionic anhydride, benzoyl chloride and the like, or most preferably acetyl chloride or methyl chloroformate. Treatment of compound 22a or 22b in the presence of a Pd0 source, carbon monoxide and an alcohol (HORb), preferably methanol, will lead to the formation of 21a. Suitable Pd0 sources include, but are not limited to, PdCl2(PPh3)2, Pd(OAc)2(PPh3)2, PdCl2(PhCN)2, Pd(OAc)2, PdCl2(P(o-tolyl)3)2, PdCl2(DDPF), Pd2(dba)3, and the like, or most preferably Pd(PPh3)4. This reaction proceeds at from room temperature to 150xc2x0 C. and is complete in from 15 min to 24 h. 
Compounds of formula 23 may be prepared using the Passerrini reaction wherein compound 1 is treated with a carboxylic acid, an isonitrile in a protic solvent as shown in Scheme X. Suitable isonitriles for the Passerrini reaction, include, but are not limited to, methyl isonitrile, ethyl isonitrile, isopropyl isonitrile, tert-butyl isonitrile, cyclohexenyl isonitrile, benzyl isonitriles and ethyl isonitriloacetate and the like. The Passerrini reaction may be performed in protic solvents or mixtures of solvents, including, but not limited to, methanol, ethanol, isopropanol, tert-butanol or water as well as aprotic solvents, including, but not limited to methylene chloride, DMSO, DMF, NMP, THF, chloroform, toluene and the like. The reaction proceeds at temperatures from 0xc2x0 C. to 80xc2x0 C. but most preferably at room temperature. Suitable carboxylic acids include, but are not limited to acetic acid, proprionic acid, formic acid, alpha-chloroacetic acid, alpha-methoxyacetic acid, butyric acid, benzoic acid and the like. Substitution of a sulfonic acid and an amine base for the carboxylic acid leads to the formation of compounds of formula 24. Suitable sulfonic acids include, but are not limited to benzene sulfonic acid or methane sulfonic acid, and the like or most preferably toluene sulfonic acid. Suitable amine bases include, but are not limited to, Et3N, DIEA, DBU, lutidine, imidazole, quinoline and the like, or most preferably pyridine. Suitable protic solvents for the formation of compound 24 include, but are not limited to, water, methanol, ethanol, n-propanol, butanol, isopropanol, allyl alcohol, tert-butanol, 2,2,2-trifluoroethanol, phenol, benzyl alcohol, ethylene glycol, methyl glycolate and the like. The Passerrini reaction may form a mixture of stereoisomers at C3xe2x80x3. The 3xe2x80x3-acylated alcohol of compounds of formula 23 may be deprotected by heating 23 in a protic or aprotic solvent with a Lewis acid catalyst (transesterification) to yield compounds of formula 24 where Rb=H. This is accomplished using conditions described for the tranesterification of compounds of formula 9 in Scheme V. The resultant 3xe2x80x3-alcohol may be acylated with suitable acylating agents including, but not restricted to, acid chlorides, carbamoyl chlorides, sulfonyl chlorides, isocyanates and the like, as described previously. 
Compounds of formula 25 may be prepared using the Ugi reaction wherein compound 1 s treated with a carboxylic acid, an isonitrile and an amine in a protic solvent as shown in Scheme X. Suitable isonitriles for the Ugi reaction, include, but are not limited to, methyl isonitrile, ethyl isonitrile, isopropyl isonitrile, tert-butyl isonitrile, cyclohexenyl isonitrile, benzyl isonitrile and ethyl isonitrilo-acetate and the like. The Ugi reaction may be performed in protic solvents or mixtures of solvents, including, but not limited to, methanol, ethanol, isopropanol, tert-butanol or water as well as aprotic solvents, including, but not limited to methylene chloride, DMSO, DMF, NMP, THF, chloroform, toluene and the like at temperatures from 0xc2x0 C. to 80xc2x0 C. but most preferably at room temperature. Suitable carboxylic acids include, but are not limited to acetic acid, proprionic acid, formic acid, alpha-chloroacetic acid, alpha-methoxyacetic acid, butyric acid, benzoic acid and the like. The Ugi reaction may be facilitated by the use of a drying agent in the reaction such as 4 xc3x85 molecular sieves. Performing the Ugi reaction employing an ortho-amino-heterocycle, an isonitrile and no carboxylic acid in a protic solvent leads to the formation of compounds of formula 26. Suitable ortho-amino-heterocycles include, but are not limited to, 2-aminopyridine, 2-aminopyrazine, 2-aminopyrimidine, 2-aminothiazole, 4-aminothiazole, 2-aminoimidazole, 2-aminooxazole, 2-amino-5-carboxamido-pyridine and the like. The ortho-amino-heterocycles may be additionally substituted with halogens, nitro groups, alkyl groups, alkoxy groups, mono-, di- and tri-fluouroalkyl groups, aryl and heteroaryl groups and the like. The Ugi reaction may form a mixture of stereolsomers at C3xe2x80x3.
Heterocycles of formula 28 and 29 may be prepared as illustrated in Scheme XI. Protection of the C7 and C24 alcohols of compound 1 (not shown) followed by oxidation of the C3xe2x80x3-aldehyde yields silyl-protected compounds of formula 5. Suitable protecting groups for the C7 and C24-alcohols include, but are not limited to, Me3Sixe2x80x94, tert-Bu(Me2)Sixe2x80x94, (nPr)3Sixe2x80x94, (iPr)3Sixe2x80x94, Ph(Me2)Si and the like or most preferably Et3Sixe2x80x94. Suitable oxidizing agents include, but are not limited to, KMnO4, NaMnO4, CrO3, AgO, Ag2O, K2Cr2O7, MnO2/NaCN, MnO2/Me3SiCN and the like or most preferably NaClO2. Amide generation using beta-hydroxy amines proceeds as described previously to form 27. Cyclization was effected by treatment of 27 with dehydrating agents, such as Martin sulfurane or Burgess reagent to obtain compounds of formula 28. Aromatization of 28 to produce 29 was acheived using DBU and BrCCl3. An additional method to prepare compounds of formula 29 was accomplished by oxidation of the beta-hydroxyl of compounds of formula 27 to the corresponding carbonyl using Dess-Martin reagent, followed by cyclo-dehydration using Ph3P/BrCl2CCCl2Br/Et2NiPr. For compounds of formula 28 or 29 where Rxcex1 or Rxcex2 contains an ester functional, this moiety may be transesterified to the corresponding allyl ester and further elaborated via its to yield the corresponding carboxylic acids and amide derivatives as previously described. Substitution of 1,3-aminoalcohols for the beta-hydroxy amines in the reactions illustrated in this scheme would yield the 6-membered version of compounds of formula 28. 
Compounds of formula 30 and 31 were prepared as illustrated in Scheme XII. Treatment of a C3xe2x80x3-dialkyl amide (e.g. compound 6 where both Rc and Rd are alkyl groups) previously protected at the C7 and C24 hydroxyls with trialkyl silyl groups with trifluoromethanesulfonic anhydride in the presence of an amine base followed by addition of appropriately substituted beta-mercapto amines produces thiazolines 30. Suitable amine bases include, but are not limited to, Et3N, DIEA, DBU, lutidine and the like or more preferably pyridine. Suitable protecting groups for the C7 and C24-alcohols include, but are not limited to, Me3Sixe2x80x94, tert-Bu(Me2)Sixe2x80x94, (nPr)3Sixe2x80x94, (iPr)3Sixe2x80x94, Ph(Me2)Si and the like or most preferably Et3Sixe2x80x94. This reaction proceeds in solvents such as MeCN, ClCH2CH2Cl, toluene, diethyl ether, THF, and the like or most preferably CH2Cl2. Aromatization of compounds of formula 30 to produce compounds of formula 31 was achieved using DBU and BrCCl3 in the presence of a desiccant such as powdered 4xc3x85 molecular sieves. The oxidation (aromatization) reaction may be performed in solvents, including, but not limited to, MeCN, CH2Cl2, ClCH2CH2Cl, toluene, diethyl ether, THF, and the like, or more preferably, dioxane. This reaction proceeds at temperatures from xe2x88x9278xc2x0 to 100xc2x0 C. For compounds of formula 30 or 31 where R60  or R62  contains an ester functional, this moiety may be transesterified to the corresponding allyl ester and further elaborated via its to yield the corresponding carboxylic acids and amide derivatives as previously described. 
Compounds of formula 32 may be prepared from compounds of formula 1 as illustrated in Scheme XIII. Treatment of compound 1 with a suitable hydroxyl amine to form an intermediate 3xe2x80x3-nitonate (compound not shown) followed by N-substituted maleimides yields the 1,3-dipolar cycloaddition product 32. Suitable hydroxyl amines for this reaction include, but are not limited to, N-hydroxy-methyl-amine, N-hydroxy-ethylamine, N-hydroxy-benzylamine, N-hydroxyproylamine, N-hydroxyaniline, methyl N-hydroxy-glycinate and the like. Additional dipolarophiles may be substituted for the N-substituted maleimides used in this dipolar cycloaddition reaction. Suitable additional dipolaiophiles include, but are not restricted to, methyl vinyl ketone, cyclohexenone, cyclopentenone, methyl acrylate, dimethyl fumarate, butenyl lactone, methyl propenylate, methyl cinnamylate, and the like. Suitable solvents for nitronate formation in include protic and aprotic solvents or mixtures thereof and include, but are not restricted to, methylene chloride, chloroform, nitromethane, nitroethane, methanol, ethanol, toluene, benzene, acetonitrile, tetrahydrofuran and the like or most preferably pyridine. The nitronate forming reaction is complete in from 15 min to 24 h at temperatures from 0xc2x0 C. to 120xc2x0 C. Preferable solvents for the dipolar cycloaddition reaction include, but are not restricted to, methylene chloride, chloroform, nitromethane, nitroethane, toluene, tetrahydrofuran or most preferably acetonitrile. The dipolar cycloaddition reaction may form a mixture of stereoisomers at C3xe2x80x3. The dipolar cycloaddition reaction with the N-substituted maleimide is complete in from 15 min to 24 h at temperatures from 0xc2x0 C. to 120xc2x0 C. 
Compounds of formula 33a may be prepared as illustrated in Scheme XIV by reductive amination of compounds of formula 1. The reductive amination may proceed using a variety of representative mono- and di-substituted amines, including but not limited to, ammonium hydroxide, methyl amine, ethyl amine, benzyl amine and substituted benzyl amines, dimethyl amine, ethylene diamine, N-ethylethylene-diamine, 2-aminoethanol, D-alanine methyl ester, 2-amino-1-phenyl-propan-1-ol, 2-amino-2,2-dimethylethanol, ortho-hydroxy-aniline, 4-phenyl-2-hydroxy-aniline, piperidine, tert-butyl amine, aniline and substituted anilines, methyl glycinate, aminoacetonitrile, methoxyl amine, methoxylamine, bis(2,2,2-trifluoroethyl)amine and the like. Suitable solvents for this reaction include but are not restricted to ethanol, toluene, tert-butanol, tetrahydrofuran, benzene, acetonitrile, methylene chloride or most preferably methanol. The reductive amination reaction may be facilitated by the addition of a dehydrating agent such as 4 angstrom sieves or the like. Suitable hydride sources include, but are not limited to NaCNBH3, LiBH4, LiAlH4, NaBH(OAc)3, DIBAL-H, nBu3SnH, Et3SiH, diborane, 9-BBN, Alpine borane, BH3.Me2S, L-Selectride, alkyl borane reagents, or most preferably, NaBH4. The reductive amination reaction yields a mixture of 1xe2x80x3,2xe2x80x3-saturated and 1xe2x80x3,2xe2x80x3-unsaturated products. The reaction proceeds at from 0xc2x0 C. to 120xc2x0 C. and is complete in from 15 min to 24 h. The preparation of compounds of formula 33c proceeded most preferrably via the intermediacy of compounds of formula 33b. Compounds of formula 33b could be deprotected to yield the primary 3xe2x80x3-amine using palladium-mediated deprotection reactions, including PdCl2(PPh3)2, Pd(OAc)2(PPh3)2, PdCl2(PhCN)2, Pd(OAc)2, PdCl2(P(o-tolyl)3)2, PdCl2(DDPF), Pd2(dba)3, and the like, or most preferably Pd(PPh3)4. Hydride sources for successful deallylation reaction included, but are not restricted to Et3SiH, Ph3SiH, nBu3SnH, Ph3SnH, catechol borane and the like, or alternatively and most preferably dimethyl barbituric acid. Starting compound 1 may have its C7- and C24-hydroxyl groups protected with silyl protecting groups. The newly formed mono- and unsubstituted 3xe2x80x3-amines of compounds of formula 33a may be acylated with suitable acylating agents including, but not restricted to, acid chlorides, carboxylic acids, carbamoyl chlorides, isocyanates, chloroformates, sulfonyl chlorides and the like under conditions described previously to form 3xe2x80x3-amides, ureas, carbamates and sulfonamides, respectively. 
The compounds of formula 33a may be further elaborated as illustrated in Scheme XV to yield compounds of formula 34, 35 and 36. Treatment of compounds of formula 33a where NRcRd is an ethylenediamine derivative (e.g. NHCRRCRRNRc) with a cyclizing agent yields compounds of formula 34. Suitable cyclization agents include but are not restricted to phosgene, thiophosgene, 1,1-thiocarbonyl-diimidazole, triphosgene, para-nitrophenyl chloroformate, methyl chloroformate and the like or most preferably 1,1-carbonyl-diimidazole. Similarly, treatment of compounds of formula 33a where NRcRd is an 1,2-aminoethanol derivative (e.g. NHCRRCRROH) with a cyclizing agent yields compounds of formula 35. In addition, treatment of compounds of formula 33a where where NRcRd is a glycine derivative (e.g. NHCRRCO2R) with an isocyanate yields compounds of formula 36. Alternatively, the isocyanate may be replaced with a thiocyanate used to prepare the corresponding thiono derivatives of compounds of formula 36. 
Compounds of formula 37 and 38 may be prepared as illustrated in Scheme XVI using olefination reactions described previously for compounds of formula 9 (Scheme V). The 2xe2x80x3,3xe2x80x3-olefin of 37 and the 1xe2x80x3,2xe2x80x3-olefin of 38 may be optionally reduced by hydrogenation using precious metal catalysts as described previously. 
Compounds of formula 39a, 39b, 40a and 40b may be prepared as illustrated in Scheme XVII. Beginning with either compounds of formula 18 where R6=H (2xe2x80x3-aldehyde) or compounds of formula 2 (1xe2x80x3-aldehyde), the C7 and C24 hydroxyls may be protected as described previously as the corresponding R3Si ethers. The 1xe2x80x3- or 2xe2x80x3-aldehydes may then be oxidized to the corresponding carboxylic acids as described for compounds of formula 5 (Scheme III) to yield the desired 2xe2x80x3- and 1xe2x80x3-carboxylic acids (39a and 40a, respectively where Rb=H). These carboxylic acids may be converted into the corresponding amides or esters as previously noted for compounds of formula 6 or 7. 
Compounds of formula 41 may be prepared as illustrated in Scheme XVIII beginning with compounds of formula 8. Treatment of the 3xe2x80x3-alcohol of 8 under Mitsunobu reaction conditions using a trisubstituted phosphine, a diazo reagent and an appropriate nucleophile will yield compounds of formula 41 where R3xe2x80x3 is halogen, azide, ORb, SRb and the like. For a review of the Mitsunobu reaction see Hughes, D. L. Organic Preparations and Procedures, Int. 1996; 28, 127-164. Suitable phosphine reagents include, but are not restricted to, tri-n-butyl phosphine and most preferably triphenyl phosphine. Suitable diazo reagents include, but are not restricted to, dimethyl diazodicarboxylate, diisopropyl diazodicarboxylate, 1,1xe2x80x2-azobis(N,N-doimethylformamide) 1,1xe2x80x2-(azodicarbonyl)dipiperidine, azodicarboxylic dimorpholide or most preferably, diethyl diazodicarboxylate. Suitable nucleophile sources for this reaction include, but are not restricted to, methanol, 2,2,2-trifluoroethanol, acetic acid, benzoic acid, trimethylsilylazide, 2-mercaptopyridine, thiolacetic acid, phenol, 2-mercaptothiazole, carbon tetrachloride and the like. The reaction may be performed in solvents including, but not limited to, benzene, toluene, 1,2-dichloroethane, tetrahydrofuran, methanol, acetonitrile and the like or most preferably methylene chloride and the reactions are complete in from 15 min to 24 h at 0xc2x0 C. to 120xc2x0 C. 
Compounds of formula 42 may be prepared as illustrated in Scheme XIV by the addition of an appropriate nucleophile to the 3xe2x80x3-aldehyde of compound 1. The C7 and C24 hydroxyls of compound 1 may be optionally protected with R3Si groups as previously described. The nucleophilic addition reaction may produce a mixture of stereoisomers at 3xe2x80x3. Suitable nucleophiles include, but are not restricted to, Grignard reagents and organolithium, organocuprates organozinc reagents, organosodium reagents, organopotassium reagents and organocerium reagents and the like. These reagents include, but are not restricted to, MeMgBr, EtLi, PhMgCl, (nPr)2CuMgI, H2Cxe2x95x90CHMgBr, 2-furfuryl lithium, BrZnCH2CO2Me, NaCH2C(O)Ph(4-Br) and the like. Suitable solvents, or mixtures of solvents for this reaction include, but are not restricted to, toluene, diethyl ether, hexanes, dioxane, 1,2-dimethoxyethane, DMSO, HMPA, DMPU and the like or most preferably, tetrahydrofuran. The reactions proceed at from xe2x88x92100xc2x0 C. to 80xc2x0 C. and are complete in from 5 min to 12 h. Replacement of compounds of formula 1 in the reaction illustrated in Scheme XIV with the 1xe2x80x3-aldehyde (compounds of formula 2) or the 2xe2x80x3-aldehyde (compounds of formula 18 where R6=H) will yield the corresponding 1xe2x80x3- and 2xe2x80x3-hydroxy derivatives. 
Compounds of formula 43 may be prepared as illustrated in Scheme XV from compounds of formula 16 where R4xe2x80x3 a is an alkyl or aryl group. Following protection of the C7 and C24 hydroxyls of compound 16 with R3Si groups as described previously, the 4xe2x80x3-ketone is treated with a strong base to generate an intermediate enolate. Suitable bases for this reaction include, but are not limited to lithium diisopropyl amine, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or most preferably lithium bis(trimethylsilyl)amide. Suitable electrophiles for this reaction include aldehydes, ketones or alkyl halides. Representative electrophiles include, but are not restricted to, formaldehyde, acetaldehyde, benzaldehyde, furfural, allyl bromide, bromoacetonitrile, alpha-bromo-tert-butyl acetate, benzyl bromide, and the like. Use of an alkyl halide (RX) in this reaction yields products of formula 43 where R3xe2x80x3=R. Use of an aldehyde (RCHO) or a ketone (RC(O)R) as the electrophile in this reaction yields products of formula 43 where R3xe2x80x3=CH(OH)R or C(OH)RR, respectively. Suitable solvents, or mixtures of solvents for this reaction include, but are not restricted to, toluene, diethyl ether, hexanes, dioxane, 1,2-dimethoxyethane, DMSO, FMPA, DMPU and the like or most preferably, tetrahydrofuran. The reactions proceed at from xe2x88x92100xc2x0 C. to 80xc2x0 C. and are complete in from 5 min to 12 h. This reaction may yield a mixture of isomers at C3xe2x80x3. 
The instant compounds are potent endo- and ecto-antiparasitic agents, particularly against helminths, ectoparasites, insects, and acarids, infecting man, animals and plants, thus having utility in human and animal health, agriculture and pest control in household and commercial areas.
The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious economic problem in domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats, fish, buffalo, camels, llamas, reindeer, laboratory animals, furbearing animals, zoo animals and exotic species and poultry. Among the helminths, the group of worms described as nematodes causes widespread and often times serious infection in various species of animals. The most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Habronema, Druschia, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia, and Oesophagostomum attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are more prevalent in the stomach while still others such as Dictyocaulus are found in the lungs. Still other parasites may be located in other tissues and organs of the body such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like. The parasitic infections known as helminthiases lead to anemia, malnutrition, weakness, weight loss, severe damage to the walls of the intestinal tract and other tissues and organs and, if left untreated, may result in death of the infected host. The compounds of this invention have activity against these parasites, and in addition are also active against Dirofilaria in dogs and cats, Nematospiroides, Syphacia, Aspiculuris in rodents, arthropod ectoparasites of animals and birds such as ticks, mites such as scabies lice, fleas, blowflies, and other biting insects in domesticated animals and poultry, such as Tenophalides, Ixodes, Psoroptes, and Hemotobia, in sheep Lucilia sp., biting insects and such migrating dipterous larvae as Hypoderma sp. in cattle, Gastrophilus in horses, and Cuterebra sp. in rodents and nuisance flies including blood feeding flies and filth flies.
The instant compounds are also useful against parasites which infect humans. The most common genera of parasites of the gastro-intestinal tract of man are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius. Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filiarial worms such as Wuchereria, Brugia, Onchocerca and Loa, Dracunuculus and extra intestinal stages of the intestinal worms Strongyloides and Trichinella. The compounds are also of value against arthropods parasitizing man, biting insects and other dipterous pests causing annoyance to man.
The compounds are also active against household pests such as the cockroach, Blatella sp., clothes moth, Tineola sp., carpet beetle, Attagenus sp., the housefly Musca domestica as well as fleas, house dust mites, termites and ants.
The compounds of this invention are also useful in combatting agricultural pests that inflict damage upon crops while they are growing or while in storage. The compounds are applied using known techniques as sprays, dusts, emulsions and the like, to the growing or stored crops to effect protection from such agricultural pests.
The compounds are also useful against insect pests of stored grains such as Tribolium sp., Tenebrio sp. and of agricultural plants such as aphids, (Acyrthiosiphon sp.); against migratory orthopterans such as locusts and immature stages of insects living on plant tissue. The compounds are useful as a nematocide for the control of soil nematodes and plant parasites such as Meloidogyne sp. which may be of importance in agriculture. The compounds are also highly useful in treating acreage infested with fire ant nests. The compounds are scattered above the infested area in low levels in bait formulations which are brought back to the nest. In addition to a direct-but-slow onset toxic effect on the fire ants, the compound has a long-term effect on the nest by sterilizing the queen which effectively destroys the nest.
The compounds of this invention may be administered in formulations wherein the active compound is intimately admixed with one or more inert ingredients and optionally including one or more additional active ingredients. The compounds may be used in any composition known to those skilled in the art for administration to humans and animals, for application to plants and for premise and area application to control household pests in either a residential or commercial setting. For application to humans and animals to control internal and external parasites, oral formulations, in solid or liquid or parenteral liquid, implant or depot injection forms may be used. For topical application dip, spray, powder, dust, pour-on, spot-on, jetting fluid, shampoos, collar, tag or harness, may be used. For agricultural premise or area application, liquid spray, powders, dust, or bait forms may be used. In addition xe2x80x9cfeed-throughxe2x80x9d forms may be used to control nuisance flies that feed or breed in animal waste. The compounds are formulated, such as by encapsulation, to lease a residue of active agent in the animal waste which controls filth flies or other arthropod pests.
Accordingly, the present invention provides a method for the treatment or prevention of diseases caused by parasites which comprises administering to a host in need of such treatment or prevention an antiparasitic effective amount of a compound of Formula I. The parasites may be, for example, arthropod parasites such as ticks, lice, fleas, mites and other biting arthropods in domesticated animals and poultry. The parasites also include helminths such as those mentioned above.
Compounds of formula I are effective in treatment of parasitic diseases that occur in other animals including humans. The optimum amount to be employed for best results will, of course, depend upon the particular compound employed, the species of animal to be treated and the type and severity of parasitic infection or infestation. Generally good results are obtained with our novel compounds by the oral administration of from about 0.001 to 500 mg per kg of animal body weight, such total dose being given at one time or in divided doses over a relatively short period of time such as 1-5 days. With the preferred compounds of the invention, excellent control of such parasites is obtained in animals by administering from about 0.025 to 100 mg per kg of body weight in a single dose. Repeat treatments are given as required to combat re-infections and are dependent upon the species of parasite and the husbandry techniques being employed. Repeat treatments may be given daily, weekly, biweekly, monthly, or longer for example up to six months, or any combination thereof, as required. The techniques for administering these materials to animals are known to those skilled in the veterinary field.
Compounds of formula I may be co-administered or used in combination with one or more other agents to the host. Co-administration or combination use includes administering all active ingredients in one formulation, for example a tablet, capsule, feed stuff, or liquid containing a compound of formula I and one or more said other agents; administering each ingredient in a separate formulation; and combinations thereof. When one or more of a compound of formula I or said other agent(s) is contained in a separate formulation, any order of administration as well as any interval between the administration of the active ingredients are within the meaning of co-administration or combination use.
Agents that may be co-administered or used in combination with compounds of formula I include any that are used in the treatment or prevention of human or animal diseases or conditions, or used in agricultural applications, or for. pest control. In a preferred embodiment, the co-administered agents are used in veterinary medicine, particularly those used in domesticated animals such as dogs and cats or other companion animals. Examples of other agents that may be co-administered with compounds of formula I are provided below. It is to be understood that the specific agents enumerated are illustrative only, and are not meant to be restrictive in any manner.
Accordingly, compounds of the present invention may be co-administered or used in combination with anthelmintic agents. These anthelmintic agents are meant to include, but not be restricted to, compounds selected from the avermectin and milbemycin class of compounds such as ivermectin, avermectin, abamectin, emamectin, eprinamectin, doramectin, milbemycin derivatives described in EPO 357460, EPO 444964 and EPO 594291, moxidectin, Interceptor(trademark) and nemadectin. Additional anthelmintic agents include the benzimidazoles such as thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and the like. Additional anthelmintic agents include imidazothiazoles and tetrahydropyrimidines such as tetramisole-levamisole, butamisole, pyrantel, pamoate, oxantel or morantel.
Compounds of this invention may be co-administered or used in combination with fipronil (FRONTLINE(trademark)); or with an insect growth regulator with molt inhibiting activity such as lufenuron (PROGRAM(trademark)) and the like; or with ecdysone agonists such as tebufenozide and the like, which induces premature molt and causes feeding to cease; or with imidacloprid (ADVANTAGE(trademark)).
Compounds of this invention may be co-administered or used in combination with avermectin or milbemycin or doramectin derivatives including selamectin (Revolution(trademark)) such as those described in U.S. Pat. 5,015,630, WO 94/15944, WO95/22552.
Compounds of this invention may be co-administered or used in combination with cyclic depsipeptides that exhibit anthelmintic efficacy such as those described in WO96/11945, WO93/19053, WO 93/25543, EP 626375, EP 382173, WO 94/19334, EP 382173 and EP 503538.
Compounds of this invention may be used in combination or be co-administered with derivatives and analogs of the general class of dioxomorpholine antiparasitic and anthelmintic agents as illustrated by WO 9615121; or with pyrethroids or organophosphates or insecticidal carbamates, such as those described in xe2x80x9cChemotherapy of Parasitic Diseasesxe2x80x9d, Campbell, W. C. and Rew, R. S, Eds., 1986; or with derivatives and analogs of the general class of paraherquamide and macfortine anthelmintic agents.
The co-administered compounds are given via routes, and in doses, that are customarily used for those compounds.
Compounds of formula I may be administered orally in a unit dosage form such as a capsule, bolus or tablet including chewable tablet, or as a liquid drench where used as an anthelmintic in mammals. The drench is normally a solution, suspension or dispersion of the active ingredient usually in water together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally, the drenches also contain an antifoaming agent. Drench formulations generally contain from about 0.001 to 0.5% by weight of the active compound. Preferred drench formulations may contain from 0.01 to 0.1% by weight. The capsules and boluses comprise the active ingredient admixed with a carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate.
Where it is desired to administer the instant compounds in a dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of active compound usually are employed. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents, and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. Such unit dosage formulations may be varied widely with respect to their total weight and content of the antiparasitic agent depending upon factors such as the type of host animal to be treated, the severity and type of infection and the weight of the host.
When the active compound is to be administered via an animal feedstuff, it is intimately dispersed in the feed or used as a top dressing or in the form of pellets or liquid which may then be added to the finished feed or optionally fed separately. Alternatively, feed based individual dosage forms may be used such as a chewable treat. Alternatively, the antiparasitic compounds of this invention may be administered to animals parenterally, for example, by intraruminal, intramuscular, intravascular, intratracheal, or subcutaneous injection in which the active ingredient is dissolved or dispersed in a liquid carrier vehicle. For parenteral administration, the active material is suitably admixed with an acceptable vehicle, preferably of the vegetable oil variety such as peanut oil, cotton seed oil and the like. Other parenteral vehicles such as organic preparation using solketal, glycerol formal, propylene glycol, and aqueous parenteral formulations are also used. The active compound or compounds are dissolved or suspended in the parenteral formulation for administration; such formulations generally contain from 0.0005 to 5% by weight of the active compound.
When the compounds described herein are administered as a component of the feed of the animals, or dissolved or suspended in the drinking water, compositions are provided in which the active compound or compounds are intimately dispersed in an inert carrier or diluent. By inert carrier is meant one that will not react with the antiparasitic agent and one that may be administered safely to animals. Preferably, a carrier for feed administration is one that is, or may be, an ingredient of the animal ration.
Suitable compositions include feed premixes or supplements in which the active ingredient is present in relatively large amounts and which are suitable for direct feeding to the animal or for addition to the feed either directly or after an intermediate dilution or blending step. Typical carriers or diluents suitable for such compositions include, for example, distillers"" dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, wheat shorts, molasses solubles, corn cob meal, edible bean mill feed, soya grits, crushed limestone and the like. The active compounds are intimately dispersed throughout the carrier by methods such as grinding, stirring, milling or tumbling. Compositions containing from about 0.005 to 50% weight of the active compound are particularly suitable as feed premixes. Feed supplements, which are fed directly to the animal, contain from about 0.0002 to 0.3% by weight of the active compounds.
Such supplements are added to the animal feed in an amount to give the finished feed the concentration of active compound desired for the treatment and control of parasitic diseases. Although the desired concentration of active compound will vary depending upon the factors previously mentioned as well as upon the particular compound employed, the compounds of this invention are usually fed at concentrations of between 0.00001 to 10% in the feed in order to achieve the desired anti-parasitic result.
In using the compounds of this invention, the individual compounds may be prepared and used in that form. Alternatively, mixtures of the individual compounds may be used, or they may be combined with other active compounds not related to the compounds of this invention.
Also included in the present invention are pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may further comprise a second active ingredient such as those described above for co-administration. Preferred second ingredient is selected from an anthelmintic agent, fipronil, imidocloprid, an insect growth regulator, or a ecdysone agonist. Said second ingredient is preferably selected from the group consisting of: ivermectin, avermectin 5-oxime, abamectin, emamectin, eprinamectin, doramectin, doramectin monosaccharide 5-oximes, fulladectin, milbemycin, milbemycin 5-oxime, moxidectin, Interceptor(trademark), nemadectin, imidacloprid, fipronil, lufenuron, tthiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, tetramisole-levamisole, butamisole, pyrantel, pamoate, oxantel and morantel.

To KMnO4 (3 g) at 25xc2x0 C. was added water (5 mL). The KMnO4 solution was cooled to 0xc2x0 C. and Al2O3 (weakly acidic, 10.8 g) was added and stirred for 5 min until thoroughly mixed. A solution of nodulisporic acid A (3 g) in CH2Cl2 (300 mL) was added dropwise via an addition funnel over 20 min. The solution was aged for an additional 20 min at 0xc2x0 C. then at 25xc2x0 C. for 90 min. The solution was filtered through a 3 inch pad of Celite using CH2Cl2 as eluant followed by EtOAc. The solvents were removed under reduced pressure at ambient temperature to yield pure title compound (2.234 g, 82%) without any additional purification.
To N-tert-butyl nodulisporamide A (50 mg) in CH2Cl2 (2 mL) at 25xc2x0 C. was added N-methylmorpholine N-oxide (50 mg) followed by 0.024 M OSO4 in water (0.31 mL). After aging the solution for 16 hr, TLC showed the presence of the desired compound and the R,R- and S,S-3xe2x80x3,4xe2x80x3-diols of N-tert-butyl nodulisporamide A. Intermediate I (10.5 mg) and the diols (36 mg) were isolated in pure form by PVLC on silica gel using 2:1 EtOAc:hexanes as eluant. The R,R- and S,S-diols were combined. To a mixture of diols (10 mg) in acetone (0.9 mL) at 25xc2x0 C. was added NaIO4 (25 mg) and the solution was allowed to age for 12 h. The solution was poured into saturated aqueous NaHCO3, extracted with EtOAc and dried (Na2SO4). Pure Intermediate I (7 mg) was obtained following PTLC on silica gel using 1/1 hexanes/EtOAc as eluant. 
To Intermediate I (560 mg) in acetonitrile (10 mL) at 25xc2x0 C. was added (Me3Si)2NH (1.8 mL) and the the solution was aged for 12 h. Additional (Me3Si)2NH (1.5 mL) and acetonitrile (3 mL) were then added. After 3 h, the solvent was removed under reduced pressure and the residue dried in vacuo for 1 h to yield pure title compound (870 mg, 100%) which required no purification. The product was characterized by proton NMR. 
To Intermediate I (750 mg) in pyridine/DMF (30 mL, 1/1) at room temperature was added Et3SiOSO2CF3 (3.2 g) and aged for 20 min. The solution was diluted with ethyl acetate, washed with saturated CuSO4(aq) (4xc3x97), water (1xc3x97), brine (1xc3x97), and dried (Na2SO4). The solution was filtered, concentrated under reduced pressure and pure product was obtained following flash chromatography on silica gel using 7/93 acetone/hexanes as eluant. The title compound thus obtained was haracterized by 1H NMR. 
To Intermediate I (420 mg) and imidazole (540 mg) in CH2Cl2 (15 mL) at 0xc2x0 C. was added (nPr)3SiCl (1 mL) dropwise. After stirring for 30 min, the solution was warmed to room temperature for an additional 30 min and then quenched with ice-water. The organic phase was separated and washed with water, dried (NaSO4), filtered and concentrated to give the pure product as a foam (620 mg). The product thus obtained was characterized by proton NMR. 
Method A
To Intermediate III (1 g) in tBuOH (25 mL) at 25xc2x0 C. was added 2-methyl-2-butene (6 mL) and stirred for 5 min. A solution of NaOCl2 (954 mg) and NaH2PO4.2H2O (1.28 g) in water (10 mL) was then added. After 4 h, the solution was poured into saturated NH4Cl(aq), extracted with CH2Cl2 (3xc3x97) and dried (Na2SO4). The solution was filtered and concentrated to dryness under reduced pressure. Pure title compound (725 mg) was obtained following flash chromatography on silica gel using gradient elution (5% to 25% EtOAc in hexanes).
Method B
A solution of KMnO4 (1.3 g) in acetone (64 mL) and pH 7 phosphate buffer (21 mL) was prepared. To Intermediate III (3.63 g) in acetone (64 mL) was added the KMnO4/buffer solution (xcx9c20 mL) and the solution was aged for 30 min. Additional KMnO4 solution (xcx9c20 mL) was added every 30 min for 2 h. The solution was then cooled to 0xc2x0 C. and 1M Na2SO3 was added until all of the KMnO4 was reacted. The mixture was filtered and washed with 15/85 MeOH/acetone (2xc3x97). The filtrate was concentrated under reduced pressure to dryness and redissolved in water. The aqueous solution was extracted with 3/7 iPrOH/CHCl3 (3xc3x97) and the organic layers were dried (Na2SO4). The solids were removed by filtration and the solution was evaporated to drynesss under reduced pressure. Pure title product (1.29 g) along with recovered starting aldehyde (xcx9c1.3 g) was obtained following flash chromatography on silica gel using 2/8 EtOAc/hexanes as eluant.
Following the procedure described for Intermediate Va and using Intermediate II, Intermediate Vb was prepared. 
Method A
To Intermediate II (821 mg) in tetrahydrofuran (THF, 8 mL) at xe2x88x9278xc2x0 C. was added L-Selectride(copyright) (Adrich, 1.07 mL, 1 M solution in THF) dropwise over 5 min. After 20 min, the solution was quenched by addition of saturated NH4Cl(aq), extracted with CH2Cl2, washed with brine and dried (Na2SO4). The solution was filtered, concentrated under reduced pressure and purifed by flash chromatography on silica gel using 15/85 EtOAc/hexanes as eluant. The pure Intermediate VIa (571 mg) thus obtained was characterized by 1H NMR.
Method B
To Intermediate II (1.0 g) in EtOAc (50 mL) at room temperature was added 10% Pd/C and a balloon atmosphere of hydrogen was established. After 5.5 h, the solution was filtered through Celite using EtOAc as eluant. The solution was concentrated under reduced pressure and purifed by MPLC chromatography on silica gel using 4/6 EtOAc/hexanes as eluant. The pure Intermediate VIa (726 mg, mobile product) and pure Intermediate VIb (70 mg, polar product) thus obtained were characterized by 1H NMR. 
To (N-diphenylmethylene)amino acetonitrile (75 mg) in THF (0.5 mL) at xe2x88x9278xc2x0 C. was added LiN(SiMe3)2 (340 xcexcL, 1.0 M solution). The yellow solution was stirred at xe2x88x9278xc2x0 C. for 5 min, placed in a 0xc2x0 C. ice bath for 5 min and then recooled to xe2x88x9278xc2x0 C. for 15 min. A solution of Intermediate II (65 mg in 0.8 mL THF) was added at xe2x88x9278xc2x0 C. After 25 min, MeSO2Cl (60 xcexcL) was added. After 10 min, triethylamine (36 xcexcL) was added and the reaction warmed first to 0xc2x0 C. for 20 min and then room temperature of 2 h. The solution was rapidly filtered without workup through a 1 inch pad of silica gel using CH2Cl2 followed by 15/85 EtOAc/hexanes as eluant. The solution was concentrated to dryness under reduced pressure and used in the next step without any further manipulation or characterization. 
Step A.
To Intermediate I (128 mg) in CH2Cl2 (10 mL) at 25xc2x0 C. was added Ph3Pxe2x95x90C(Et)CO2CH2CHxe2x95x90CH2 (320 mg). The solution was aged for 2 days and then additional Ph3Pxe2x95x90C(Et)CO2CH2CHxe2x95x90CH2 (320 mg) was added. After one additional hour, the solution was purified without workup by flash chromatography on silica gel using 6/4 EtOAc/hexanes as eluant to yield pure allyl ester of Intermediate VIIIb (124 mg, 84%). The purified allyl ester of Intermediate VIIIa was characterized by proton NMR and mass spectrometry [m/z: 734.1. (M++1)].
Step B.
To the 5xe2x80x3-allyl ester of Step A (160 mg) in 1/3 THF/CH2Cl2 (8 mL) at 25xc2x0 C. was added (Ph3P)4Pd (13 mg) and morpholine (160 mg). The solution was aged for 6 h and the solution was purified without workup by flash chromatography on silica gel using 1/9 MeOH/CH2Cl2 as eluant to yield pure Intermediate VIIIa (112 mg, 74%). The purified Intermediate VIIIa was characterized by proton NMR and mass spectrometry [m/z: 693.4 (M++1)].
Intermediates VIIIb and VIIIc were similarly prepared following the procedurc for Intermediate VIIIa and using Ph3Pxe2x95x90C(n-Pr)CO2CH2CHxe2x95x90CH2 and Ph3Pxe2x95x90C(n-Bu)CO2CH2CHxe2x95x90CH2, respectively.